Portal de investigação
Cellular and Mitochondrial Toxicity of Tolcapone, Entacapone, and New Nitrocatechol Derivatives
Data de publicação:
Data Ahead of Print:
Autores da FMUP
Participantes de fora da FMUP
- Pinto, M
- Silva, TB
- Sardao, VA
- Simoes, R
- Albuquerque, B
- Oliveira, PJ
- Valente, MJ
- Remiao, F
- Fernandes, C
- Borges, F
Unidades de investigação
Abstract
Nitrocatechols are the standard pharmacophore to develop potent tight-binding inhibitors of catechol O-methyltransferase (COMT), which can be used as coadjuvant drugs to manage Parkinson's disease. Tolcapone is the most potent drug of this class, but it has raised safety concerns due to its potential to induce liver damage. Tolcapone-induced hepatotoxicity has been attributed to the nitrocatechol moiety; however, other nitrocatechol-based COMT inhibitors, such as entacapone, are safe and do not damage the liver. There is a knowledge gap concerning which mechanisms and chemical properties govern the toxicity of nitrocatechol-based COMT inhibitors. Using a vast array of cell-based assays, we found that tolcapone-induced toxicity is caused by direct interference with mitochondria that does not depend on bioactivation by P450. Our findings also suggest that (a) lipophilicity is a key property in the toxic potential of nitrocatechols; (b) the presence of a carbonyl group directly attached to the nitrocatechol ring seems to increase the reactivity of the molecule, and (c) the presence of cyano moiety in double bond stabilizes the reactivity decreasing the cytotoxicity. Altogether, the fine balance between lipophilicity and the chemical nature of the C1 substituents of the nitrocatechol ring may explain the difference in the toxicological behavior observed between tolcapone and entacapone.
© 2024 American Chemical Society.
Dados da publicação
- ISSN/ISSNe:
- 2575-9108, 2575-9108
- Tipo:
- Article
- Páginas:
- 1637-1649
- Link para outro recurso:
- www.scopus.com
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE American Chemical Society
Citações Recebidas na Web of Science: 1
Citações Recebidas na Scopus: 2
Documentos
- Não há documentos
Filiações
Keywords
- tolcapone; entacapone; nitrocatechols; hepatotoxicity; mitochondria; lipophilicity
Financiamento
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Citar a publicação
Pinto M,Silva TB,Sardao VA,Simoes R,Albuquerque B,Oliveira PJ,Valente MJ,Remiao F,Soares P,Fernandes C,Borges F. Cellular and Mitochondrial Toxicity of Tolcapone, Entacapone, and New Nitrocatechol Derivatives. ACS Pharmacol Transl Sci. 2024. 7. (5):p. 1637-1649.
